【作者】 高界铭；

【导师】 张兴栋； 顾忠伟；

【作者基本信息】 西南交通大学 ， 材料学， 2008， 博士

【摘要】 癌症严重威胁人类健康,化疗是目前癌症治疗的主要手段之一,但往往因较大的毒副作用不得不中断治疗而贻误治疗时机。纳米药物载体对肿瘤组织具有高度靶向性、能实现药物缓控释放、降低毒副作用、同时提高难溶药物的溶解率和吸收率,因此,纳米载药系统有可能成为优异的癌症化疗制剂。9-硝基喜树碱(9-NC)是有效的拓扑异构酶Ⅰ抑制剂,临床试验已取得很大成功,并被FDA批准用于胰腺癌治疗。为了增强9-NC内酯环稳定性,改善其亲水性能,避免呕吐、腹泻、骨髓抑制等毒副作用发生,本研究采用共聚物胶束包覆9-NC并实现其靶向、缓控释放。论文工作的主要内容如下:1、以辛酸亚锡为催化剂,聚乙二醇单甲醚(mPEG)引发D,L-丙交酯(LA)本体开环聚合,得到亲水链段相同而疏水链段长度不同的两亲性嵌段共聚物mPEG-b-PLA(PELA):运用~1H-NMR、GPC、FT-IR、DSC和静态接触角对共聚物进行表征。2、1,3-丙二醇和碳酸二乙酯为原料,合成了三亚甲基碳酸酯(TMC)单体;在160℃、[Monomer]/[Catalyst]=2000、聚合反应12 h条件下,辛酸亚锡作催化剂,TMC、LA和mPEG共聚,制备了不同疏水链段长度及不同疏水组分比例(PTMC/PLA)的系列共聚物mPEG-b-P(LA-co-TMC)(PETLA),采用~1H-NMR、GPC、FF-IR、DSC和静态接触角对共聚物进行表征。3、合成了六元环状碳酸酯单体9-苯基-2,4,8,10-四氧螺[5,5]十一烷-3-酮(CC);以异丙醇铝为催化剂,mPEG、LA和CC共聚,制备了不同疏水链段长度和疏水组分比例的系列共聚物mPEG-b-P(LA-co-CC)(PECLA);PECLA经脱保护后与叶酸偶联,得到新型嵌段共聚物FA-PECLA,紫外测得平均每个共聚物分子FA-pECLA8上偶联了1.52个叶酸分子。4、以9-硝基喜树碱(9-NC)为模型药物,采用溶剂挥发成膜法制备了M、MT和FA-MC系列胶束(分别对应于共聚物PELA、PETLA和FA-PECLA);以胶束M3为研究对象,考察了水浴温度、三蒸水用量、搅拌速度、投药量及共聚物结构组成对载药量、胶束粒径的影响,优化了胶束制备工艺。5、运用DLS、TEM、荧光分光光度计、~1H-NMR、GPC、XPS、WAXD、UV、HPLC等多种手段分析评价了胶束的尺寸、形貌、临界胶束浓度、结构组成、药物分布状态、胶束稳定性、内酯环稳定性、体外药物释放行为和载药胶束在大鼠体内的组织分布情况。本论文采用三种生物相容性好的降解性高分子PELA、PETLA和PECLA分别构建了三种纳米胶束药物控释系统,并对胶束的性质、药物稳定性、体外释药行为和动物体内实验进行了系统的表征。论文创新性主要表现为:(1)采用多种双亲性生物降解高分子嵌段共聚物胶束构建了9-硝基喜树碱的纳米控释系统,使9-硝基喜树碱的释放接近零级释放;(2)所构建的纳米胶束药物控释系统极大地提高了9-硝基喜树碱的稳定性,成功解决了9-硝基喜树碱在使用中易失去其生物活性的问题;(3)成功获得了以叶酸为靶向基团的新型纳米胶束药物控释系统,为抗肿瘤药物的主动靶向治疗提供新选择。本研究工作的意义在于:通过具有良好生物相容性的降解性聚酯-聚乙二醇嵌段共聚物和9-硝基喜树碱构建抗肿瘤药物的纳米控释系统,较全面的研究了该系统的药物控释行为,为进一步研究乃至临床试验奠定了基础;胶束药物载体能降低化疗药物对病人的毒副作用,为癌症病人的治疗提供了一种潜在的更为安全和有效的方法。更多还原

【Abstract】 Chemotherapy is the main approach for cancer therapy at present as cancer threatens human health seriously,but it is often interrupted by serious poisonous side effect so that the patients often miss the optimal treatment opportunity. Nanomedicine carriers will be tile outstanding chemotherapy agent for tumor treatment since it owns many advantages:the high targeting property,controlled release,reducing the poisonous side effect,and the improvement of dissolving and absorbing capacity for drugs.9-nitro-20（s）-camptothecin（9-NC）,an effective topoisomeraseⅠinhibitor,has achieved remarkable success in clinical trials and been given approval by FDA for pancreatic cancer treatment.In order to improve lactone stability and hydrophilic performance of 9-NC and avoid poisonous side effects such as nausea,diarrhea and marrow suppression,this research work will focus on 9-NC encapsulation by copolymer micelles and realize the drugs targeting and controlled release delivery.The primary coverage of this dissertation is as following:1^st,methoxy poly（ethylene glycol）-b-poly（D,L-lactide）（mPEG-b-PLA, PELA）with varied PLA block and constant mPEG block were synthesized by ring-opening polymerization of D,L-lactide（LA）,initiating by mPEG and catalyzing with stannous octoate.Copolymer characterization was carded out with 1^H-NMR,GPC,FT-IR,DSC,and statistic contact angle apparatus.2^nd,trimethylene carbonate（TMC）was synthesized from 1,3-propanediol and diethyl carbonate.Copolymer mPEG-b-poly（LA-co-TMC）（PETLA）was synthesized by copolymerization of TMC,LA and mPEG with catalyst stannous octoate under the following conditions:160℃,[Monomer]/[Catalyst]=2000, t=12 h.Copolymers with different hydrophobic length and different hydrophobic components ratios（PTMC/PLA）were prepared and characterized by ¹H-NMR, GPC,FT-IR,DSC and static contact angle.3^rd,six member cyclic carbonate monomer 9-phenyl-2,4,8,10-tetraoxaspiro -[5,5]undecane-3-one（CC）was synthesized.Taking aluminium isopropoxide as catalyst,copolymers PECLA with different hydrophobic length and hydrophobic component ratios（PCC/PLA）were prepared by copolymerization of tri-components:D,L-lactide,mPEG and CC.Novel block copolymer FA-PECLA was obtained by deprotection of PECLA and conjugating with folic acid. Ultraviolet spectra detection illustrated that 1.52 folic acid molecule were coupled with each molecule of FA-PECLA8 averagely.4^th,micelles M,MT and FA-MC（corresponds separately to copolymer PELA,PETLA and FA-PECLA）were prepared by solvent evaporation method and 9-NC was used as model drug.Taking micelle M3 for studying,micellar preparation processes were optimized by evaluating the effect of bath temperature, tri-distilled water amount,the stirring speed,drug input weight,and copolymer composition on the drug loading content and the diameter of micelles.5^th,Characterization on the micellar properties in aspects of size, morphology,critical micelle concentration,structure and composition,drug distribution condition,micellar stability,lactone stability,drug release profile in vitro and tissue distribution in rats were carried out with DLS,TEM,fluorescence spectrophotometer,¹H-NMR,GPC,XPS,WAXD,UV,and HPLC apparatus.In this dissertation,three kinds of micellar delivery systems constructed from three kinds of well biodegradable polymer PELA,PETLA and PECLA were established.Comprehensive characterizations including the micellar properties, drug stability,drug release behaviors in vitro and distribution in vivo were carried out.Innovative achievements could be concluded in the following aspects:（1） Three kinds of 9-NC encapsulated drug delivery systems were constructed on the base of the varied amphiphilic biodegradable copolymers,and the drug release rates from the micelles were nearly in zero order.（2）The lactone stability of 9-NC was improved greatly after the encapsulation by micelles and the labile bioactivity of 9-NC in use could be conquered.（3）Novel controlled release system based on folic acid targeted micelles was established and this provided novel opportunity for active targeted delivery of anti-cancer drugs. The significance of this research work lies in:systemic performance studies of 9-NC loaded controlled release systems were performed by the construction of 9-NC loaded micelles based on well compatible and biodegradable copolymer polyester-poly（ethylene glycol）and 9-NC,this work offered the foundational data for further study or further clinical research.On the other hand,micellar carriers could decrease the poisonous side effect to the patient and provided a more safe and effective chemotherapy approach for cancer treatment.更多还原